The applicant is a general surgeon whose clinical and research focus is pancreatic cancer. She plans to study the role of the developmental signaling factor Sonic hedgehog in pancreatic tumorigenesis. The career development plan focuses on acquiring basic knowledge and experimental skills in pancreatic cancer/pathology and development. Drs. Andrew Warshaw, mentor, internationally known for his work in pancreatic cancer, and Drucilla Roberts, co-mentor, an accomplished independent investigator in GI development and hedgehog signaling, have committed their expertise and resources to guiding her program. An informal advisory committee, consisting of the pancreatic developmental biologist Dr. Douglas Melton and pancreatic/ GI pathologist Dr. Gregory Lauwers, will augment the candidate's training in mouse modeling and pancreatic development and pathology. The combined resources of the Massachusetts General Hospital and Harvard Medical School provide a rich research environment for this young investigator's development. Hedgehog (Hh) signaling, an essential pathway during embryonic pancreatic development whose misregulation has been implicated in several forms of cancer, may also be an important mediator in human pancreatic carcinoma. SHH is abnormally expressed in pancreatic cancer and its precursor lesions, pancreatic intra-epithelial neoplasia (PanlN). Pancreata of mice in which Shh is misexpressed in the pancreatic endoderm develop abnormal tubular structures, a phenocopy of human PanlN-1 and -2. Furthermore, Hedgehog signaling remains active in cell lines from primary and metastatic pancreatic adenocarcinomas, and inhibition of Hh signaling induces apoptosis and blocks proliferation both in vitro and in vivo. Thus, the Hh pathway may be important in both initiation and maintenance of pancreatic cancer. The candidate's proposed aims are: 1) to develop a Tet conditional mouse model to determine whether misexpression of Shh in the adult pancreas is sufficient to cause pancreatic neoplasia; 2) to determine the prevalence of expression of Shh and pathway members in human cancer by real-time PCR; and 3) to determine whether inactivation of the HH pathway can influence the biologic behavior of pancreatic cancer in a murine xenograft model using fresh surgical explants. This will allow us to better understand the role of this pathway in human pancreatic cancer, so that it may be exploited for new diagnostic and therapeutic modalities. [unreadable] [unreadable]